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Title: 1α,25-dihydroxyvitamin D3 stimulates human SOST gene expression and sclerostin secretion

Journal Article · · Molecular and Cellular Endocrinology
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  1. Univ. of Adelaide, SA (Australia)
  2. Univ. of South Australia, Adelaide, SA (Australia)
  3. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Physical and Life Sciences Directorate; Univ. of California, Merced, CA (United States)
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Sclerostin, the SOST gene product, is a negative regulator of bone formation and a positive regulator of bone resorption. Here, in this study, treatment of human primary osteoblasts, including cells differentiated to an osteocyte-like stage, with 1α,25-dihydroxyvitaminD3 (1,25D) resulted in the dose-dependent increased expression of SOST mRNA. A similar effect was observed in human trabecular bone samples cultured ex vivo, and in osteocyte-like cultures of differentiated SAOS2 cells. Treatment of SAOS2 cells with 1,25D resulted in the production and secretion of sclerostin protein. In silico analysis of the human SOST gene revealed a single putative DR3-type vitamin D response element (VDRE) at position -6216 bp upstream of the transcription start site (TSS). This sequence was confirmed to have strong VDRE activity by luciferase reporter assays and electrophoretic mobility shift analysis (EMSA). Sequence substitution in the VDR/RXR half-sites abolished VDRE reporter activity and binding of nuclear proteins. A 6.3 kb fragment of the human proximal SOST promoter demonstrated responsiveness to 1,25D. The addition of the evolutionary conserved region 5 (ECR5), a known bone specific enhancer region, ahead of the 6.3 kb fragment increased basal promoter activity but did not increase 1,25D responsiveness. Site-specific mutagenesis abolished the responsiveness of the 6.3 kb promoter to 1,25D. We conclude that 1,25D is a direct regulator of human SOST gene and sclerostin protein expression, extending the pathways of control of sclerostin expression. At least some of this responsiveness is mediated by the identified classical VDRE however the nature of the transcriptional regulation by 1,25D warrants further investigation.

Research Organization:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Organization:
USDOE National Nuclear Security Administration (NNSA); National Health and Medical Research Council of Australia (NHMRC); National Institutes of Health (NIH)
Grant/Contract Number:
AC52-07NA27344; ID565372; DK075730
OSTI ID:
1891707
Alternate ID(s):
OSTI ID: 1249889
Report Number(s):
LLNL-JRNL-837178; 1056922
Journal Information:
Molecular and Cellular Endocrinology, Vol. 413; ISSN 0303-7207
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 30 works
Citation information provided by
Web of Science

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Cited By (9)

Hormonal Regulation of Osteocyte Perilacunar and Canalicular Remodeling in the Hyp Mouse Model of X-Linked Hypophosphatemia: OSTEOCYTE PERILACUAR AND CANALICULAR REMODELING IN HYP MICE journal November 2017
Vitamin D–regulated osteocytic sclerostin and BMP2 modulate uremic extraskeletal calcification journal July 2019
Sclerostin, an emerging therapeutic target for treating osteoporosis and osteoporotic fracture: A general review journal January 2016
DObesity: Relationship between vitamin D deficiency, obesity and sclerostin as a novel biomarker of bone metabolism journal September 2019
Sclerostin and chronic kidney disease journal December 2017
Control of Bone Homeostasis by the Wnt Inhibitor Sclerostin journal June 2016
Relationship between plasma levels of sclerostin, calcium–phosphate disturbances, established markers of bone turnover, and inflammation in haemodialysis patients journal December 2018
Role of the Wnt/β-Catenin Pathway in Renal Osteodystrophy journal January 2018
1,25-Dihydroxyvitamin D Alone Improves Skeletal Growth, Microarchitecture, and Strength in a Murine Model of XLH, Despite Enhanced FGF23 Expression journal February 2016

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59 BASIC BIOLOGICAL SCIENCES
biological sciences
medical sciences
vitamin D
vitamin D response element
SOST
sclerostin
osteocyte
gene regulation
promoter